Galactocerebrosidase deficiency induces an increase in lactosylceramide content: A new hallmark of Krabbe disease?

Abstract

Galactocerebrosidase (GALC) hydrolyses galactose residues from various substrates, including galactosylceramide, psychosine (galactosylsphingosine), and lactosylceramide. Its severe deficiency has been associated with the accumulation of psychosine, a toxic molecule with detergent-like features, which alters membrane structures and signalling pathways, inducing the death of oligodendrocytes and a sequence of events in the nervous system that explain the appearance of many clinical signs typical of Krabbe disease. Nevertheless, new evidence suggests the existence of other possible links among GALC action, myelination, and myelin stability, apart from psychosine release. In this study, we demonstrated that lactosylceramide metabolism is impaired in fibroblasts isolated from patients with Krabbe disease in the absence of psychosine accumulation. This event is responsible for the aberrant and constitutive activation of the AKT/prolin-rich AKT substrate of 40 kDa (PRAS40) signalling axis, inducing B cell lymphoma 2 (BCL2) overexpression and glycogen synthase kinase 3 beta (GSK-3β) inhibition. In addition, nuclear factor E2-related factor 2 (NRF2) showed increased nuclear translocation. Due to the relevance of these molecular alterations in neurodegeneration, lactosylceramide increase should be evaluated as a novel marker of Krabbe disease, and because of its significant connections with signalling pathways.

• Authors: Nadia Papini, Chiara Giallanza, Loredana Brioschi, Francesca Romana Ranieri, Paola Giussani, Laura Mauri, Maria Grazia Ciampa, Paola Viani, Cristina Tringali
• Journal: The international journal of biochemistry & cell biology (Int J Biochem Cell Biol) Vol. 145 Pg. 106184 (04 2022) ISSN: 1878-5875 [Electronic] Netherlands
• PMID: 35217188 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier Ltd. All rights reserved.

Chemical References

• AKT1S1 protein, human
• Adaptor Proteins, Signal Transducing
• BCL2 protein, human
• Lactosylceramides
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• Proto-Oncogene Proteins c-bcl-2
• Psychosine
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Proto-Oncogene Proteins c-akt

Topics

• Adaptor Proteins, Signal Transducing
• Glycogen Synthase Kinase 3 beta
• Humans
• Lactosylceramides (metabolism)
• Leukodystrophy, Globoid Cell (genetics, metabolism, pathology)
• NF-E2-Related Factor 2
• Proto-Oncogene Proteins c-akt
• Proto-Oncogene Proteins c-bcl-2
• Psychosine (metabolism)